Process for the preparation of 5-bromo-2-fluorobenzeneboronic acid

ABSTRACT

A process is disclosed for the preparation of 5-bromo-2-fluorobenzeneboronic acid, which is useful as an intermediate in the preparation of a non-ester pyrethroid compound. The compound can be, for example, a fluoroolefin, which is useful as a pesticide.

This is a divisional of application Ser. No. 08/871,025 filed on Jun. 6,1997 now U.S. Pat. No. 5,962,742, the entire disclosure of which ishereby incorporated by reference.

BACKGROUND AND SUMMARY OF THE INVENTION

5-Bromo-2-fluorobenzeneboronic acid is an important intermediate in thesynthesis of a number of non-ester pyrethroid compounds.5-Bromo-2-fluorobenzeneboronic acid and processes for its preparationare described in U.S. Pat. No. 5,068,403 and Pesticide Science, 28, pp.25-34 (1990), which are incorporated herein by reference. Thosereferences disclose that 5-bromo-2-fluoro-benzeneboronic acid isprepared from 2,4-dibromofluoro-benzene. However,2,4-dibromofluorobenzene is not entirely satisfactory for use in thecommercial manufacture of 5-bromo-2-fluorobenzeneboronic acid.

2,4-Dibromofluorobenzene is commercially available as a mixturecontaining seventy percent 2,4-dibromofluorobenzene and thirty percent3,4-dibromofluorobenzene. When that mixture is used to prepare5-bromo-2-fluorobenzeneboronic acid, at most, only a 70% yield isobtainable based on the total amount used. In addition, to obtain highpurity 5-bromo-2-fluorobenzeneboronic acid, a time-consumingpurification step is required to remove impurities such as3,4-dibromofluorobenzene. A process that avoids the use of2,4-dibromofluorobenzene would provide a great improvement over the artprocesses.

It is therefore an object of the present invention to provide a processfor the preparation of 5-bromo-2-fluorobenzeneboronic acid which avoidsthe use of 2,4-dibromofluorobenzene.

The present invention provides a process for the preparation of5-bromo-2-fluorobenzeneboronic acid which comprises lithiating1-bromo-4-fluorobenzene with a lithium base in the presence of a solventto form (5-bromo-2-fluorophenyl)lithium, reacting(5-bromo-2-fluorophenyl)lithium with a tri(C₁-C₆alkyl) borate to form adi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate, and hydrolyzing thedi(C₁-C₆alkyl) 5-bromo-2-fluorobenzene-boronate. It has been found thatthe process of this invention is more effective and efficient than theprior art processes, and avoids the use of 2,4-dibromo-fluorobenzenewhich is commercially availably only as an impure mixture.

The present invention also provides a process for the preparation of afluoroolefin compound of formula I

wherein

Ar is phenyl optionally substituted with any combination of from one tothree halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy orC₁-C₄haloalkoxy groups, or

1- or 2-naphthyl optionally substituted with any combination of from oneto three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy orC₁-C₄haloalkoxy groups;

R is hydrogen and R₁ is cyclopropyl, or R and R₁ are each independentlyC₁-C₄alkyl, or R and R₁ are taken together with the carbon atom to whichthey are attached to form a cyclopropyl group.

The configuration of the hydrogen atom and the fluorine atom about thedouble bond is mutually trans. The process comprises lithiating1-bromo-4-fluorobenzene with a lithium base in the presence of a solventto form (5-bromo-2-fluorophenyl)lithium, reacting(5-bromo-2-fluorophenyl)lithium with a tri(C₁-C₆alkyl) borate to form adi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate, hydrolyzing thedi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate to form5-bromo-2-fluorobenzeneboronic acid, oxidizing5-bromo-2-fluorobenzeneboronic acid to form 5-bromo-2-fluorophenol,reacting 5-bromo-2-fluorophenol with bromobenzene and a base such assodium hydride to form 5-bromo-2-fluorophenyl ether, reacting5-bromo-2-fluorophenyl ether with magnesium, and reacting the resultingcompound in the presence of a transition metal catalyst such as acuprous halide, cuprous cyanide or Li₂CuCl₄ to form the desiredfluoroolefin of formula I. The fluoroolefin compound is useful in apesticide composition.

Compounds of Formula I may have a trans or cis configuration of thehydrogen and fluorine atom about the double bond. Compounds having atrans configuration are preferred, and are prepared by using thereactant III (as described below) having a trans configuration. Toprepare compounds of Formula I with a cis configuration, a reactant IIIhaving a cis configuration is used. To prepare compounds of Formula Ihaving a mixture of trans and cis configurations, a reactant III havinga mixture of trans and cis configurations is used.

The invention is described in the following specific embodiments:

1. A process for preparing 5-bromo-2-fluorobenzeneboronic acid, theprocess comprises lithiating 1-bromo-4-fluorobenzene to form(5-bromo-2-fluorophenyl)lithium; reacting(5-bromo-2-fluorophenyl)lithium with a tri(C₁-C₆alkyl) borate to form adi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate; and hydrolyzing thedi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate.

2. The process of embodiment 1 wherein the lithiating step is at atemperature of less than about 0° C.

3. The process of embodiment 2 wherein the temperature is less thanabout −40° C.

4. The process of embodiment 1 wherein the 1-bromo-4-fluorobenzene inthe lithiating step is reacted with a lithium base.

5. The process of embodiment 4 wherein the lithium base is a lithiumdialkylamide or a lithium cyclic amide.

6. The process of embodiment 4 wherein the 1-bromo-4-fluorobenzene inthe lithiating step is reacted with the base in the presence of asolvent.

7. The process of embodiment 6 wherein the solvent is an ether.

8. The process of embodiment 1 wherein the tri(C₁-C₆alkyl) borate istrimethyl borate.

9. The process of embodiment 1 wherein the di(C₁-C₆alkyl)5-bromo-2-fluorobenzeneboronate is hydrolyzed with an organic or mineralacid.

10. The process of embodiment 9 wherein the organic or mineral acid isan aqueous acid.

11. A process for the preparation 5-bromo-2-fluorobenzeneboronic acidwhich comprises lithiating 1-bromo-4-fluorobenzene with a lithium basein the presence of a solvent to form (5-bromo-2-fluorophenyl)lithium,reacting (5-bromo-2-fluorophenyl)lithium with tri(C₁-C₆alkyl) borate toform a di(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate, and hydrolyzingthe di(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate.

12. The process according to embodiment 11 wherein1-bromo-4-fluorobenzene is lithiated with the lithium base at atemperature below about: 0° C.

13. The process according to embodiment 12 wherein the temperature isbelow about −40° C.

14. The process according to embodiment 11 wherein the lithium base is alithium diaLkylamide or a lithium cyclic amide.

15. The process according to embodiment 14 wherein the lithium base islithium diisopropyl amide.

16. The process according to embodiment 11 wherein the solvent is anether.

17. The process according to embodiment 16 wherein the ether istetrahydrofuran.

18. The process according to embodiment 11 wherein the tri(C₁-C₆alkyl)borate is trimethyl borate.

19. The process according to embodiment 11 wherein the di(C₁-C₆alkyl)5-bromo-2-fluorobenzeneboronate is hydrolyzed with an aqueous organicacid or an aqueous mineral acid.

20. A process for the preparation 5-bromo-2-fluorobenzeneboronic acidwhich comprises lithiating 1-bromo-4-fluorobenzene with a lithium baseselected from the group consisting of a lithium dialkylamide and alithium cyclic amide in the presence of an ether to form(5-bromo-2-fluorophenyl)lithium with a tri(C₁-C₆alkyl) borate to form adi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate, and hydrolyzing thedi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate with an aqueous organicor mineral acid.

21. A process for preparing a fluoroolefin compound having the formla

wherein

Ar is phenyl optionally substituted with any combination of from one tothree halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy orC₁-C₄haloalkoxy groups, or 1- or 2-naphthyl optionally substituted withany combination of from one to three halogen, C₁-C₁alkyl,C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups;

R is hydrogen and R₁ is cyclopropyl, or R and R₁ are each independentlyC₁-C₄alkyl, or R and R₁ are taken together with the carbon atom to whichthey are attached to form a cyclopropyl group; and

the configuration of the hydrogen atom and the fluorine atom about thedouble bond is mutually trans. The process comprises

lithiating 1-bromo-4-fluorobenzene with a lithium base in the presenceof a solvent to form (5-bromo-2-fluorophenyl)lithium,

first reacting (5-bromo-2-fluorophenyl)lithium with a tri(C₁-C₆alkyl)borate to form a di(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate,

hydrolyzing the di(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate to form5-bromo-2-fluorobenzeneboronic acid,

oxidizing 5-bromo-2-fluorobenzeneboronic acid to form5-bromo-2-fluorophenol,

second reacting 5-bromo-2-fluorophenol with bromobenzene and a base toform 5-bromo-2-fluorophenyl ether,

third reacting 5-bromo-2-fluorophenyl phenyl ether with magnesium toform the corresponding magnesium bromide, and

fourth reacting the magnesium bromide with a compound having the formula

 wherein Ar, R and R₁ are as described above and Q is OC(O)CH₃ or Br inthe presence of a transition metal catalyst.

22. The process of embodiment 21 wherein the base in the second reactingstep is sodium hydride.

DETAILED DESCRIPTION OF THE INVENTION

The process preferably comprises lithiating 1-bromo-4-fluorobenzene withat least about one molar equivalent of a lithium base in the presence ofa solvent preferably at a temperature below about 0° C., more preferablybelow about −40° C., to form (5-bromo-2-fluorophenyl)lithium, reacting(5-bromo-2-fluorophenyl)lithium with at least about one molar equivalentof a tri(C₁-C₆alkyl) borate to form a di(C₁-C₆alkyl)5-bromo-2-fluorobenzeneboronate, and hydrolyzing the di(C₁-C₆alkyl)5-bromo-2-fluorobenzene boronate with at least about two molarequivalents of an aqueous acid to form the desired5-bromo-2-fluorobenzene-boronic acid. The reaction scheme is shown inFlow Diagram I.

Advantageously, the process of this invention overcomes the problemsassociated with the use of impure 2,4-dibromofluorobenzene by using1-bromo-4-fluorobenzene. By avoiding the use of impure2,4-dibromofluorobenzene, the process of this invention provides5-bromo-2-fluorobenzeneboronic acid in higher yield and higher puritythan the less effective and less efficient art processes.

Lithium bases suitable for use in the process of this invention includelithium secondary amide bases such as lithium dialkylamides, lithiumcyclic amides, lithium arylalkylamides and lithium bis(alkylsilyl)amidesand alkyl lithiums such as n-butyl lithium, s-butyl lithium, andtert-butyl lithium. Preferred lithium bases include lithiumdialkylamides such as lithium diisopropylamide and lithiumisopropylcyclohexylamide, lithium cyclic amides such as lithium2,2,6,6-tetramethylpiperidine, lithium arylalkylamides such as lithiumphenylmethylamide, and bis(alkylsilyl)amides such as lithiumbis(trimethylsilyl)amide, with lithium diisopropylamide and lithium2,2,6,6-tetramethylpiperidine being more preferred.

Solvents suitable for use in the process of the present inventioninclude organic solvents which do not react undesirably with any of thecompounds present in the reaction mixture. Preferred organic solventsinclude ethers such as tetrahydrofuran, diethyl ether,1,2-dimethoxyethane, and mixtures thereof, with tetrahydrofuran beingmore preferred.

Preferred tri(C₁-C₆alkyl) borates include trimethyl borate, triethylborate, tri-n-butyl borate and triisopropyl borate with trimethyl boratebeing more preferred.

The di(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate compound ispreferably hydrolyzed with an aqueous organic acid such as acetic acid,propionic acid and butyric acid or an aqueous mineral acid such ashydrochloric acid and sulfuric acid.

In order to facilitate a further understanding of the invention, thefollowing example is presented to illustrate more specific detailsthereof. The invention is not to be limited thereby except as defined inthe claims.

EXAMPLE 1 Preparation of 5-Bromo-2-fluorobenzeneboronic Acid

A solution of lithium diisopropylamide (165 mL of a 2.0 M solution intetrahydrofuran, 0.33 mol) in tetrahydrofuran (600 mL) at −70° C. istreated with 1-bromo-4-fluorobenzene (33.0 mL, 0.30 mol), stirred at−70° C. for 90 minutes and added to a solution of trimethyl borate (41.0mL, 0.36 mol) in diethyl ether (300 mL) at −70° C. The resultingsolution is stirred at −70° C. for 15 minutes, warmed to 15° C. over 90minutes, treated with acetic acid (51.5 mL, 0.9 mol) and water (375 mL),and stirred at room temperature for 30 minutes. The organic layer isseparated and the aqueous layer is extracted with ether. The organicextracts are combined with the organic layer and the resulting solutionis washed sequentially with 10% hydrochloric acid and brine, dried overanhydrous magnesium sulfate and concentrated in vacuo to give the titleproduct as an off-white solid (65 g, 99% yield).

Advantageously, the present invention also provides a process for thepreparation of a fluoroolefin compound of formula I

wherein

Ar is phenyl optionally substituted with any combination of from one tothree halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy orC₁-C₄haloalkoxy groups, or 1- or 2-naphthyl optionally substituted withany combination of from one to three halogen, C₁-C₄alkyl,C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups;

R is hydrogen and R₁ is cyclopropyl, or R and R₁ are each independentlyC₁-C₄alkyl, or R and R₁ are taken together with the carbon atom to whichthey are attached to form a cyclopropyl group; and

the configuration of the hydrogen atom and the fluorine atom about thedouble bond is mutually trans.

The process comprises lithiating 1-bromo-4-fluorobenzene with a lithiumbase in the presence of a solvent to form(5-bromo-2-fluorophenyl)lithium, reacting(5-bromo-2-fluorophenyl)lithium with a tri(C₁-C₆alkyl) borate to form adi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate, hydrolyzing thedi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate to form5-bromo-2-fluorobenzeneboronic acid, oxidizing5-bromo-2-fluorobenzeneboronic acid to form 5-bromo-2-fluorophenol,reacting 5-bromo-2-fluorophenol with bromobenzene and a base such as asodium hydride to form 5-bromo-2-fluorophenyl ether, reacting5-bromo-2-fluorophenyl phenyl ether with magnesium to form a magnesiumbromide of formula II, and reacting the formula II compound with analkene compound of formula III in the presence of a transition metalcatalyst such as cuprous halide, cuprous cyanide or Li₂CuCl₄ to form thedesired fluoroolefin of formula I. The fluoroolefin compound is usefulin a pesticide composition.

The reaction scheme for the preparation of the fluoroolefin compound isshown in Flow Diagram II.

FLOW DIAGRAM II

I claim:
 1. In a process for preparing a fluoroolefin compound havingthe formula

wherein Ar is phenyl optionally substituted with any combination of fromone to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy orC₁-C₄haloalkoxy groups, or 1- or 2-naphthyl optionally substituted withany combination of from one to three halogen, C₁-C₄alkyl,C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups; R is hydrogen andR₁ is cyclopropyl, or R and R₁ are each independently C₁-C₄alkyl, or Rand R₁ are taken together with the carbon atom to which they areattached to form a cyclopropyl group; and the configuration of thehydrogen atom and the fluorine atom about the double bond being mutuallytrans, which process comprises oxidizing 5-bromo-2-fluorobenzeneboronicacid to form 5-bromo-2-fluorophenol, first reacting5-bromo-2-fluorophenol with bromobenzene and a base to form5-bromo-2-fluorophenyl phenyl ether, second reacting5-bromo-2-fluorophenyl phenyl ether with magnesium to form thecorresponding magnesium bromide, and third reacting the magnesiumbromide with a compound having the structural formula

 wherein Ar, R and R₁ are as described above, and Q is OC(O)CH₃ or Br,in the presence of a transition metal catalyst selected from the groupconsisting of a cuprous halide, cuprous cyanide and Li₂CuCl₄, wherein,prior to the oxidizingz step, the improvement comprises lithiating1-bromo-4-fluorobenzene with at least about one molar equivalent of alithium base in the presence of a solvent to form(5-bromo-2-fluorophenyl) lithium, reacting(5-bromo-2-fluorophenyl)lithium with a tri (C₁-C₆alkyl) borate to form adi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate, and hydrolyzing thedi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate to form5-bromo-2-fluorobenzeneboronic acid.
 2. In a process for preparing afluoroolefin compound having the formula

wherein Ar is phenyl optionally substituted with any combination of fromone to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy orC₁-C₄haloalkoxy groups, or 1- or 2-naphthyl optionally substituted withany combination of from one to three halogen, C₁-C₄alkyl,C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups; R is hydrogen andR₁ is cyclopropyl, or R and R₁ are each independently C₁-C₄alkyl, or Rand R₁ are taken together with the carbon atom to which they areattached to form a cyclopropyl group; and the configuration of thehydrogen atom and the fluorine atom about the double bond being mutuallytrans, which process comprises oxidizing 5-bromo-2-fluorobenzeneboronicacid to form 5-bromo-2-fluorophenol, first reacting5-bromo-2-fluorophenol with bromobenzene and a base to form5-bromo-2-fluorophenyl phenyl ether, second reacting5-bromo-2-fluorophenyl phenyl ether with magnesium to form thecorresponding magnesium bromide, and third reacting the magnesiumbromide with a compound having the structural formula

 wherein Ar, R and R₁ are as described above, and Q is OC(O)CH₃ or Br,in the presence of a transition metal catalyst selected from the groupconsisting of a cuprous halide, cuprous cyanide and Li₂CuCl₄, wherein,prior to the oxidizing step, the improvement comprises lithiating1-bromo-4-fluorobenzene with at least about one molar equivalent of alithium base selected from the group consisting of a lithiumdialkylamide and a lithium cyclic amide in the presence of an ether toform (5-bromo-2-fluorophenyl)lithium, reacting(5-bromo-2-fluorophenyl)lithium with a tri(C₁-C₆alkyl) borate to form adi(C₁-C6alkyl) 5-bromo-2-fluorobenzeneboronate, and hydrolyzing thedi(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronate with an aqueous organicacid or an aqueous mineral acid to form 5-bromo-2-fluorobenzeneboronicacid.
 3. The process of claim 1 wherein the base in the first reactingstep is sodium hydride.
 4. The process of claim 1 or 2 wherein1-bromo-4-fluorobenzene is lithiated with the lithium base attemperature below about 0° C.
 5. The process of claim 4 wherein thetemperature is below about −40° C.
 6. The process of claim 1 or 2wherein the lithium base is a lithium dialkylamide or a lithium cyclicamide.
 7. The process of claim 6 wherein the lithium base is lithiumdiisopropyl amide.
 8. The process of claim 1 or 2 wherein the solvent isan ether.
 9. The process according to claim 8 wherein the ether istetrahydrofuran.
 10. The process according to claim 1 or 2 wherein thetri(C₁-C₆alkyl) borate is trimethyl borate.
 11. The process according toclaim 1 or 2 wherein the di(C₁-C₆alkyl) 5-bromo-2-fluorobenzeneboronateis hydrolyzed with an aqueous organic acid or an aqueous mineral acid.